Vav1 is essential for HIF-1 activation in vascular response to ischemic stress. Vav1 is a tyrosine phosphorylation-dependent guanine nucleotide exchange factor (GEF) for small RhoGTPase. It has been thought to be restricted to hematopoietic cells in normal development. However, we for the first time found Vav1 expression in vascular endothelium and regulates vascular homeostasis under stress. Vascular response to hypoxia is a major determinant of organ function, which is particularly critical for vital organs such as the heart. Recently, we identified Vav1 as a key vascular regulator of hypoxia and essential for HIF-1 activation. It regulates HIF-1a stabilization through the p38/Siah2/PHD3 pathway. Consequently, Vav1 deficient mice are predisposed to sudden death under cardiac ischemia with increased coronary endothelial apoptosis. Moreover, Vav1 binds to VEGFR1 that carries Vav1 to lysosomes for degradation in normoxia. Hypoxia upregulates Vav1 through inhibition of protein degradation. These findings reveal that regulation of Vav1 by hypoxia is analogous to HIF-1a regulation. Both proteins are constitutively produced allowing for rapid responses when stress occurs, and constantly degraded in normoxia. Hypoxia stabilizes Vav1, which is required for HIF-1a accumulation. Together they mediate the vascular response to hypoxia and maintain tissue homeostasis. This work has been submitted for publication. Vav1 accumulates in endothelium and contributes to aging associated vascular dysfunction. Vascular dysfunction occurs as a consequence of biological aging and is a major risk factor for cardiovascular diseases. Recently, we observed that Vav1 deficiency in mice led to eNOS dependent vascular dilation and a greater response to acetylcholine in aorta. Molecular analysis revealed that knockdown of Vav1 in endothelial cells increased Sirt1, which deacetylated eNOS, and subsequently activated eNOS and induced NO production. Conversely, ectopic expression of Vav1 inhibited Sirt1 expression and eNOS activation. These data suggest a negative role of Vav1 on eNOS activation through inhibition of Sirt1. Interestingly, Vav1 accumulates in cultured endothelial cells and mouse aorta during aging, which correlates with a reduction of Sirt1 and increased eNOS acetylation/inactivation and reduced NO production. Loss of Vav1 protected mice from aging associated vascular dysfunction as measured by eNOS dependent vascular relaxation, hypertension and arterial stiffness. This work has been submitted for publication. Vav1 regulates mesenchymal stem cell (MSC) differentiation decision between adipocyte and chondrocyte via Sirt1. Using a Vav1 reporter mice we generated, we characterized Vav1 expression in vivo. We detected expression of Vav1 in MSCs. Interestingly, loss of Vav1 in MSCs led to spontaneous adipogenic but impaired chondrogenic differentiation, and accordingly Vav1 null mice displayed an increase in fat content and a decrease in cartilage. Mechanistically, loss of Vav1 reduced the level of Sirt1, which was responsible for an increase of acetylated PPARg. As acetylation activates PPARg, it increased C/EBPa expression and promoted adipogenesis. On the other hand, loss of Vav1 resulted in an increase of acetylated Sox9, a target of Sirt1. As acetylation represses Sox9 activity, it led to a dramatic reduction of collagen 2a1, a key regulator in chondrocyte differentiation. Together this study reveals a novel function of Vav1 in regulating MSC cell fate decisions for differentiation through Sirt1. Sirt1 deacetylates PPARg and Sox9, two key mediators that control adipocyte and chondrocyte differentiation. The acetylation status of PPARg and Sox9 has opposite effects on its activity, thereby controlling cell fate decision. This work was published in Stem Cells in 2016. Several years ago, we identified a novel gene, NK4, that amplifies vascular inflammation and potentiates sepsis development. However, what is NK4 and how it regulates cellular function is not known. The small GTPase and Ras homolog Rap1 plays a central role in vesicle trafficking, exocytosis, signaling and cell adhesion. Recently, we found that NK4, also known as interleukin 32, is a late endosomal/multivesicular body (MVB) associated GEF for Rap1. NK4 bound Rap1 and promoted the exchange of GDP for GTP, activating Rap1 and eliciting actin sprouting. Through a combination of live cell and super-resolution imaging, we demonstrate the presence of the NK4/Rap1 complex at exocytotic blebs. NK4/Rap1 association required a small helical domain conserved among Rap GEFs, flanked by regions homologous to ApoE, indicating a novel GEF architecture. Functionally, activation of NK4 results in expulsion of pathogens from epithelial and endothelial cells via exocytosis. These works will be summarized for publication.